Asymmetric Biosynthesis of Key Aromatic Intermediates in the Synthesis of an Endothelin Receptor Antagonist

The feasibility of five potential biocatalytic routes were investigated for the chiral synthesis of key intermediates of an experimental endothelin receptor antagonist. Two asymmetric bioreductions of a ketoester and a chlorinated ketone to their corresponding chiral alcohol yielded very encouraging leads. Pichia delftensis (strain MY1569) and Rhodotorula piliminae (ATCC 32762) were found to respectively bioreduce the esterified ketone and chlorinated substrate to their corresponding (S) alcohol with enantiomeric excesses > 98% and > 99% respectively. When scaled up in laboratory bioreactors (23-liter scale), both processes produced the desired (S) alcohol intermediate with elevated yield, about 88% and 97% for the ketoester and chloroketone respectively, Investigative chemical syntheses employing the (S) ester alcohol showed that unfavorable racemization occurred during the subsequent synthetic steps. However, the use of the (S) chloroalcohol as chiral synthon for the production of the endothelium receptor antagonist was successfully demonstrated at a preparative scale.